N-methylsulphites and n-methanesulphinic acid salts of 1-aryl-2, 3-dialkyl-4-alkylaminopyrazolones



Patented Mar. 19, 194i) UNITED STATES.

N-METH'YLSULPHITES' AND N-METHANE- SULPHINICACID- SALTS F LABEL-2,3-DIALKYLA-ALKYLAMINOPYRAZOLONES Max Bockmiihl, Walter Krohs, Fritz Racke,and

Kurt Windisch, Frankfort on the Main- Hochst, Germany, asslgnors toWinthrop Chemical Company, Inc., New York, N. Y., a corporation'of NewYork No Drawing. Application .iuly '21, 1938, Serial PATE '9 No.220,496. In Germany July 24, 1937 comm. (o1; 260-31 0)" wherein X standsfor a branched alkyl radical, for instance for one of the followingradicals:

The present invention relates to N-methylsulphites andN-methanesulphinic acidsalts of 1-aryl-2.3-dialkyli-alkylaminopyrazolones.

In U. S. Patent No. 1,426,348, and German Pat- 5 ents Nos. 476,643 and476,663, also in U. S. Patent 2,078,440 in connection with German PatentNo. 617,237 there is described inter alia the manufacture ofN-methylsulphites and N-methane-. sulphinic acid salts of1-aryl-2.3-dialkyl-4-alkyl- 1o aminopyrazolones. All the compoundsobtain able by that manufacture are N-methylsulphites orN-methanesulphinic acid salts of secondary amines and the alkyl radicalof which situated at the amino-nitrogen is straight, such as forinstance methyl, ethyl and the like.

We have found that N-methylsulphites and N-methanesulphinic acid saltsof 1-aryl-2.3-dialkyl-4-alkyl-aminopyrazolones which contain a branchedaliphatic radical at the 4-nitrogenare compounds which, in comparisonwith the known compounds, have,in addition ,to' the antipyretic action,a narcotic action and therefore are suitable for the use as analgesics;the invention consists in the manufacture of these compounds 5containing a branched aliphatic radical.

The compound may be made in various ways. For exampletheaminopyrazolones named are directly condensed with formaldehydebisulphite or formaldehyde sulphoxylate. Instead of starting fromformaldehyde bisulphite there may be used formaldehyde and bisulphite ina desired sequence. If the aminopyrazolones are first condensed withformaldehyde the methylene-biscompounds of the amines are formed whichmay then be transformed into the N-Inethylsulphites by the addition of afurther quantity of formaldehyde and of bisulphite. Furthermore, theproc- ECH; Hi-Y cur-on:

-"-Y stands for a mem 'sisting of and Me standing for a 9. -oto Me metalof the group consisting NT OFFICE CHz-CH: v 1

her of the group conof alkali metals or alkaline earth metals, saidcompounds being white powders soluble in water with a neutral reactionto litmus paper and sol- I uble in methyl alcohol and ethyl alcohol. 7

The following examples serve to illustrate the invention but they arenot intended to limit it thereto; the parts are by weight; parts byvolume have the same ratio to parts by weight that i the litre has tothe kilo:

(1) 1 phenyl 2.3 dimeth yl 4 isopropylamino-5-pyrazolone melting at C.is prepared by causing l-phenyl 2.3 dimethyl 4 aminopyrazolone to reactwith isopropylbromide.

lOO parts thereof are introduced into the reaction solution, heated to50 (3., prepared from parts of a sodium bisulphite solution of 37.8

per cent. strength and 40 parts ofa formaldehyde solution of 30 percent. strength. After the pyrazolone has dissolved, 300 parts of alcoholare added, the solution is mixed with animal charcoal and filtered andthe sodium salts of 1 phenyl 2.3 dimethyl 5 pyrazolone 4isopropylaminomethylsulphurous acid is precipi- (2) 16 parts of thesodum salt of 1-phenyl-' 2.3 dimethyl-5-pyrazolone4-aminomethylsulphurous acid and 3 parts of sodium' carbonate are dissolved in50 parts of water and the solution is heated to 40 C. with 10 parts ofdi-isopropylsulphate, while stirring, until thefevolution' of carbondioxide has ceased. The solution is then evaporated under reducedpressure -so;.as to obtain a dry mass which is recrystallized fromdilute alcohol. The compound is identical with that obtained asdescribed in-Examplda, 1.

(3) 20 parts of 1-phenyl-2.3-dimethylA-isopropylamino-5-pyrazolone aredissolved in dilute alcohol and the solution is mixed with 8 parts of aformaldehyde solution of 30 per cent. strength. After the solution hasbeen stirred for some time 22 parts of sodium bisulphite of 37.8 percent. strength are added and the whole is further stirred for one hourat 10 C. After the solvent has been evaporated under reduced pressureand the residue has been recrystallized from dilute alcohol a compoundis obtained which is identical with that of Example 1.

The same compound is obtained by adding first the solution of sodiumbisulphite to the dilute alcoholic solution of the amine and thenrunning in the formaldehyde solution at 40 C. while stirring.

(4) 10 parts of 2. formaldehyde solution of 30 per cent. strength areadded to a solution of 20.3 parts of1-phenyl-2.3-dirnethyl-4-amino-5-pyrazolone in 50 parts of water, thewhole is stirred for some time and then mixed with 20 parts ofdi-isopropyl sulphate and 6 parts of sodium carbonate. After thesolution has been stirred for some time at 40 C. 28 parts of a solutionof sodium bisulphite of 37.8 per cent.- strength are added and the wholeis further stirred for some time at the same temperature. By evapcratingthe solvent under reduced pressure and recrystallizing the residue fromdilute alcohol the same compound is obtained as in Example 1.

(5) 49 parts of 1-phenyl-2.3-dimethyl-4-isopropylamino-5-pyrazolone aredissolved in parts of dioxane, 76 parts by volume of a formal.- dehydesolution containing 395 grams of formaldehyde per liter are added and12.5 parts of sulphur dioxide are introduced into the solution whilecooling. After the introduction has been finished the reaction isallowed to proceed for 15 minutes at room temperature and 400 parts ofdioxane are then added. Thel-phenyl-2.3-dimethyl-5-pyrazolone-4-isopropylaminomethane sulphonicacid crystallizes which is filtered with suction and washed with dioxaneand petroleum ether.

16 parts of this acid are introduced at 40 C. into a suspension of 2parts of calcium carbonate in 15 parts of water. Dissolution occurs withevolution of carbon dioxide. The whole is filtered. alcohol is added,the mass is cooled and the calcium salt which precipitates is filteredwith suction. It melts at C. with decomposition.

(6) By heating for 3 hours at 100 C. 1- phenyl-2.3-dimethyl 4aminopyrazolone with 2-bromobutane in. an alcoholic solution thelpheny1-2.3-dimethyl .4 secondarybutylaminopyrazolone, melting at 78 C.,is obtained.

-dimethyhS-pyrazolone-4l-secondary-butylaminomethanesulphonic acid Whichprecipitates is filteredwith suction.

8 parts of the acid so obtained are introduced into .a mixture of 2.4parts of caustic soda solution of 30 per cent. strength and 10 parts ofabsolute alcohol.

After the mixture has been filtered: ether isadded, the whole isfiltered with suction and the sodium salt of the l-phenyl-2.3-edimethyl-5-pyrazolone 4 secondary-butyl aminomethylsulphurous acidis recrystallized from a'mixture of acetone and absolute alcohol. Theproduct melts at 166 C. with decomposition.

.(7) 245 parts of l-phenyl-2.3-dimethyl-4iso- 'propylamino-5-pyrazoloneare introduced at 0. into a solution of 15.2 parts of sodiumformaldehyde sulphoxylate in 15 parts of water. After the Whole hasdissolved the solution is evaporated to dryness under reduced pressureand the sodium salt of the 1-phenyl-2.3-dimethyl-5 pyrazolone 4isopropylaminomethanesulphinic acid is recrystalized from dilutealcohol.

8) 1 phenyl 2.3-dimethy1-4-isobutylamino- 5-pyrazolone, melting at 71C., is prepared by reducing a mixture of 1-phenyl2.3-dimethyl-4-amino-5-pyrazo1one and isobutylaldehyde. 55 parts thereof are introducedat 50 C. into a reaction solution of 55 parts prepared from a sodiumbisulphite solution of 37.7 per cent. strengthand 20 parts of aformaldehyde solution of 30 per cent. strength. After the pyrazolone hasdissolved the solution is evaporated to dryness under reducedpressureand the sodium salt of .the l-phenyl-2.3-dimethyl-5-pyrazolone4-isobutylaminomethylsulphurous acid thus obtainedis recrystallized fromethyl acetate. It melts at 170 C. If recrystallized from moist ethylacetate a product containing water of crystallization is obtained.melting at 70 C. to 75 C.

We claim:

1. The compounds of the following formula:

CHr-Y wherein X stands for a branched unsubstituted lower alkylhydrocarbon radical and Y stands for a member of the group consisting ofII S-OMe and Me standing for a metal of the group consisting of alkalimetals or alkaline earth metals. said compounds being White powderssoluble in water with a neutral reaction to litmus paper and soluble inmethyl alcohol and ethyl alcohol.

2. The compound of the following formula:

I o s 1 7 v5' CH; I 06 \N-CH; DOB-OHr-N-zC-CH; on

10 forming a white powder soluble in water with a neutral reaction tolitmus paper and soluble in methyl alcoholand ethyl alcohol. v v 3. Thecompound'of thefollowing formula:

OH; o6 N-on; on-N-azz-cm 20 CE: (I?

GHr-O. S.O.Na

forming a white powder soluble in water witha neutralreaction to litmuspaper and soluble in methyl alcohol and ethyl alcohol. V e

4. The compound of the following formula:-

forming a white powder soluble in water with a neutral reaction tolitmus paper and'soluble 15 in methyl alcohol and ethyl alcohol.

--MAX BOCKMETHL,

. WALTER KROHS.

FRITZ RACKE. I v KURT WINDISCH.

